Lung cancer is the most devastating malignancy in the world. Beyond genetic research, epigenomic studies—especially investigations of microRNAs—have grown rapidly in quantity and quality in the past decade. This has enriched our understanding about basic cancer biology and lit up the opportunities for potential therapeutic development. In this review, we summarize the involvement of microRNAs in lung cancer carcinogenesis and behavior, by illustrating the relationship to each cancer hallmark capability, and in addition, we briefly describe the clinical applications of microRNAs in lung cancer diagnosis and prognosis. Finally, we discuss the potential therapeutic use of microRNAs in lung cancer.

Several anaplastic lymphoma kinase inhibitors (ALKIs) have demonstrated excellent efficacy on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and also better adverse effect (AE) profiles compared to cytotoxic chemotherapy in advanced stage anaplastic lymphoma kinase (ALK) rearrangement-positive non-small cell lung cancer (NSCLC) in phase III randomized clinical trials (RCTs). We conducted this systematic review and network meta-analysis to provide a ranking of ALKIs for treatment-naïve ALK-positive patients in terms of PFS, ORR, and AEs. In addition, a sub-group analysis of treatment benefits in patients with baseline brain metastasis was also conducted. Contrast-based analysis was performed for multiple treatment comparisons with the restricted maximum likelihood approach. Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being the best (Prbest) reference. All next-generation ALKIs were superior to crizotinib in PFS but lorlatinib and brigatinib had increased AEs. The probability of lorlatinib being ranked first among all treatment arms was highest (SUCRA = 93.3%, Prbest = 71.8%), although there were no significant differences in pairwise comparisons with high- (600 mg twice daily) and low- (300 mg twice daily) dose alectinib. In subgroup analysis of patients with baseline brain metastasis, low-dose alectinib had the best PFS (SUCRA = 87.3%, Prbest = 74.9%). Lorlatinib was associated with the best ranking for ORR (SUCRA = 90.3%, Prbest = 71.3%), although there were no significant differences in pairwise comparisons with the other ALKIs. In addition, low-dose alectinib had the best safety performance (SUCRA = 99.4%, Prbest = 97.9%). Lorlatinib and low-dose alectinib had the best PFS and ORR in the overall population and baseline brain metastasis subgroup, respectively. Low-dose alectinib had the lowest AE risk among the available ALKIs. Further head-to-head large-scale phase III RCTs are needed to verify our conclusions.

The interaction between tumors and their microenvironments leads to a vicious cycle, which strengthens both immune suppression and cancer progression. The present study demonstrates for the first time that tumor-associated dendritic cells (TADCs) are a source of resistin, which is responsible for increasing lung cancer epithelial-to-mesenchymal transition. In addition, large amounts of resistin in the condition medium (CM) of TADCs increase cell migration and invasion, as well as the osteolytic bone metastatic properties of lung cancer cells. Neutralization of resistin from TADC-CM prevents the advanced malignancy-inducing features of TADC-CM. Significantly elevated levels of resistin have been observed in mice transplanted with lung cancer cells, tumor-infiltrating CD11c⁺ DCs in human lung cancer samples and lung cancer patients’ sera. Induction of lung cancer progression by TADC-derived resistin is associated with increased expression of Wolf–Hirschhorn syndrome candidate 1 (WHSC1), a histone methyltransferase. Resistin-induced WHSC1 increases the dimethylation of histone 3 at lysine 36 and decreases the trimethylation of histone 3 at lysine 27 on the promoter of Twist, resulting in an enhancement of the expression of Twist. Knockdown of WHSC1 by small interfering RNA transfection significantly decreases resistin-mediated cancer progression by decreasing the upregulation of Twist, suggesting that WHSC1 plays a critical role in the regulation of Twist by epigenetic modification. Furthermore, mice that received antiresistin antibodies showed a decreased incidence of cancer development and metastasis. These findings suggest that TADC-derived resistin may be a novel candidate in promoting the development of lung cancer.

Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT₁ receptor (CysLT₁R). CysLT₁R antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLT₁R antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLT₁R antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLT₁R was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLT₁R antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Compared to cytotoxic chemotherapy, afatinib has been shown to have better efficacy in the treatment of non-small cell lung cancer harboring EGFR mutations. However, 40 mg daily as the initial dose is often accompanied by serious adverse drug reactions (ADRs) and 28 to 53.3% of patients required a dose reduction. No previous study has compared the clinical efficacy and ADRs of different initial doses (40 mg vs. 30 mg daily) of afatinib in lung cancer treatment. Patients with stage IV lung adenocarcinoma diagnosed and treated in two Kaohsiung Medical University-affiliated hospitals in Taiwan between May 2014 and August 2016 were identified and followed until December 2016. Demographic characteristics, responses, progression-free survival (PFS), overall survival (OS), and ADRs were recorded. A total of 48 patients with stage IV lung adenocarcinoma harboring susceptible EGFR mutations who received afatinib as their first-line therapy were enrolled. Patients using 30 mg daily as the initial dose tended to be older and female and have a smaller body size. The patients using 30 mg of afatinib daily as their initial dose had a similar response rate to those receiving 40 mg daily (76% vs. 95%, p = 0.0862) and the same disease control rate (100% vs. 100%, p = 0.1486). The PFS was similar between the patients receiving 30 mg or 40 mg of afatinib daily (median PFS: 469 vs. 443 days, log-rank p = 0.8418). Patients receiving 30 mg daily had a significantly lower incidence of diarrhea than those using 40 mg daily (41% vs. 100%, p < 0.0001). An initial afatinib dose of 30 mg daily had similar response and progression-free survival rates as an initial dose of 40 mg daily, but resulted in fewer serious ADRs in this study.